It is the principle aim of this investigation to delineate the mechanisms involved in digitalis-induced ventricular arrhythmia and to provide greater insight into the methods to prevent or treat digitalis cardiotoxicity without affecting the drug's therapeutic action. From our previous experiments performed during the last grant period, it has now become obvious that our initial view that digitalis-induced arrhythmia is due in part to drug-induced increase in adrenergic nerve activity requires reconsideration. Towards this end we shall continue to analyze the role of the adrenergic nervous system in the development of digitalis-induced ventricular arrhythmias but our conceptual approach will be directed towards developing the contention that it is not just an increase in neural activity but rather it is the development of discoordinated activity in the adrenergic nervous system induced by digitalis that is responsible. This inhomogeneity in neural activity is then imposed on the heart causing arrhythmia. Nonuniformity in neural activity and the nature of the patterns of neural discharge associated with digitalis-induced arrhythmia will be one of the major studies in this investigation. As part of this investigation, we will explore the time sequence of the development of nonuniform activity in both neural discharge as well as the heart and their relation to the development of ventricular arrhythmia. It will be important to determine how essential the presence of nerves, both in the intact and isolated heart is in the development of nonuniform activity and arrhythmia in the heart. Of special importance to our study will be characterization of the role of the adrenal medulla in the genesis of digitalis arrhythmia. An effect on the adrenal medulla may be a important determinant in the capcity of digoxin to induce arrhythmia while with ouabain the medulla seems to play only a minor role. Thus, it seems all glycosides do not produce arrhythmia by the same mechanisms. Further studies of these differences in glycoside action is part of the investigation. Not only will we study the importance of digitalis action on the adrenergic nervous-medulla sites in the genesis of arrhythmia but also the direct action the glycoside exerts on the heart will be evaluated.